PROJECT SUMMARY/ABSTRACT A growing body of pre-clinical literature suggests beta-adrenergic antagonist medications may be effective for treating addiction. Studies show that administration of these medications can reduce preference for environments associated with drugs of abuse via associative learning paradigms (i.e. conditioned place preference) and protect against reinstatement following extinction. Although the neural mechanisms of these effects have been carefully examined in rodent models, very little research has examined the neurobehavioral effects of propranolol on responses to drug use stimuli in humans. A recent study in our laboratory indicated that exposure to images of personal drug-use contexts activates the same brain regions involved in the expression of conditioned place preference in rodent models. This Imaging ? Science Track Award for Research Transition (I/START) grant will extend that work to examine the effects of propranolol on neural and behavioral responses to drug-use contexts in human smokers. The overarching goal of this project is to elucidate the brain mechanisms through which propranolol may exert an effect on human smoking behavior and to obtain preliminary data regarding its potential clinical use. Forty adult smokers will identify and photograph environments they associate with smoking and environments they associate with abstinence using a procedure we have developed and validated. They will then be randomly assigned to receive either propranolol (40-mg) or placebo immediately prior to undergoing a functional magnetic resonance imaging (fMRI) scan. During the scan, they will view images of the personalized smoking environments they previously photographed, as well as standard smoking environments and proximal smoking cues (e.g. lighters, ashtrays). Immediately following the scan, participants will complete a laboratory task that assays their ability to resist smoking in exchange for monetary incentives while exposure to personalized smoking environments continues. We hypothesize that propranolol will attenuate brain activations in response to personal smoking environments across several target brain regions identified in prior research, reduce covariation of activations across these regions (i.e. functional connectivity) and increase willingness to resist smoking in exchange for monetary incentives. Additional exploratory analyses will examine the relationship between neural activation/connectivity and smoking urge/behavior. Results of this I/START grant will provide support for a subsequent R01 application investigating the neural mechanisms of propranolol and similar medications in the context of larger-scale trials. Accordingly, this research has strong potential for translation. It will provide valuable information on the neural underpinnings of the effects of beta adrenergic medications on responses to drug-use contexts and their relationship with smoking behavior. It will also inform the development and study of both novel and established pharmacological treatments for cigarette smoking and other addictions.